ICU Primary Snippet – iNO & Prostacyclins

Notes by Dr Madhuri Anupindi

Nitric oxide:

Mechanism of action:

• Rapidly absorbed into pulmonary circulation  Activates guanylate cyclase (soluble enzyme in cytosol version – natural version is membrane found protein)  converts GTP into cGMP  activates protein kinase G  inhibits IP3-mediated release of calcium, phosphorylates voltage gated ca channels (inactivates), phosphorylates phospholamban (regulates ca pump) which increases ca uptake in sarcoplasmic reticulum  smooth muscle relaxation  pulmonary vasodilation in ventilated regions  hopefully increases VQ matching

Potential adverse effects

• Methemoglobinemia
  • Nitric oxide reacts with oxyhaemoglobin to form metHb and nitrate and with deoxyhaemoglobin to form nitrosyl haemoglobin  this is converted to methaemoglobin on exposure to oxygen.
  • Nitric oxide can also combine with oxygen and water to produce nitrogen dioxide, and nitrite, which can interact with oxyhaemoglobin to produce methaemoglobin and nitrate formation of nitrogen dioxide depends on the nitric oxide concentration, fio2 and the amount of time they are exposed to each other
• Adverse effects from nitrogen dioxide: worsens ARDS, bronchiolitis, pneumonitis, airway injury
• Renal failure (RR 1.6)
• Rebound pulmonary hypertension and hypoxia with abrupt withdrawal
• Platelet inhibition
• Increased blood flow to the left heart  may cause APO if LV dysfunction.

Inhaled prostacyclin:

Mechanism of action:

• Derivative of arachidonic acid
• activates G protein-coupled receptors on platelets, and vascular endothelial cells,
• activates adenylate cyclase,
• increases intracellular cAMP
• inhibits further platelet activation + activates protein kinase A
• phosphorylates and inhibits myosin light chain kinase
• smooth muscle relaxation and vasodilatation
• cAMP inhibits platelet aggregation (prevents increased intracellular calcium)

Potential adverse effects

• System vasodilatation
  • Flushing
  • Headache
  • Hypotension + tachycardia
• Bronchospasm
• May increase the risk of bleeding (inhibits platelet function)
• Glycine (sterile diluent) can block expiratory filter
• increases resistance
• Decreased gastric emptying
• Inhibition of gastric acid secretion